Response of pemphigus vulgaris to anti-CD20 antibody therapy (rituximab) may be delayed.
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Adult↗
Biomedical subjects
C Hoyle
Publications and source records attributed to C Hoyle.
Second autologous transplant with cyclosporin/interferon alpha-induced graft versus host disease for patients who have failed first-line consolidation.
The prognosis for patients with non-Hodgkin's lymphoma (NHL) and advanced Hodgkin's disease (HD) who relapse following autologous transplant is poor. We report on a pilot study designed to evaluate the feasibility of using Cyclosporin A and interferon alpha to induce autologous GVHD following a second autologous transplant for relapsed lymphoma. In all, 10 patients entered the study with median age 46.5 years. Diagnosis was NHL (n=7) or Hodgkin's lymphoma (n=3). All had relapsed from a prior autologous transplant. The second transplant was well tolerated by all patients. Histological changes consistent with cutaneous GVHD developed in 30% of patients at a median of 22.5 days from transplant and settled spontaneously in all cases. Five patients have died (four from progressive disease) at a median 7 months from second transplant. Five patients are still alive and in complete remission at a median of 20 months from transplant. Median overall survival for the group is 13.5 months and median relapse-free survival has not been reached at 42 months. This is a well-tolerated regimen for use in this poor-risk group of patients with lymphoma. The overall survival and event-free survival are encouraging, however further studies are necessary.
Adult↗
Non-MHC-restricted cytotoxic cells: their roles in the control and treatment of leukaemias.
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Animals↗
Prokaryote multidrug efflux proteins of the major facilitator superfamily: amplified expression, purification and characterisation.
In bacterial genomes 3-12% of open reading frames are predicted to encode membrane transport proteins. These proteins can be vital for antibiotic efflux, protein/ toxin secretion, cell nutrition, environmental sensing, ATP synthesis, and other functions. Some, such as the multidrug efflux proteins, are potential targets for the development of new antibacterials and also for applications in biotechnology. In general membrane transport proteins are poorly understood, because of the technical difficulties involved in isolating sufficient protein for elucidation of their structure-activity relationships. We describe a general strategy for the amplified expression, purification and characterisation of prokaryotic multidrug efflux proteins of the 'Major facilitator superfamily' of transport proteins, using the Bacillus subtilis multidrug resistance protein, 'Bmr', as example.
Amino Acid Sequence↗
Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice.
We have developed culture conditions for the efficient expansion of cytotoxic effector cells from peripheral blood mononuclear cells (PBMNCs) by the timed addition of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and the monoclonal antibody (MoAb) OKT3. These cells, termed cytokine-induced killer (CIK) cells, are composed primarily of T cells, and the population of cells with the greatest cytotoxic activity is an otherwise rare population of CD3(+)CD56(+) cells that expand dramatically under these culture conditions. CIK cells were expanded from PBMNCs from 13 patients with chronic myeloid leukemia (CML). These cultures contained a variable number of T cells at the start of the culture (median 44%, range 1% to 64%), yet after 21 to 28 days of culture, virtually all of the cells were CD3(+) T cells (median 97%, range 90% to 99%). The CD3(+)CD56(+) subset of cells expanded significantly (median 25-fold, range 2.2- to 525-fold). CIK cells from all patients showed cytotoxicity against the tumor cell lines OCI-LY8 and K562. In four patients the expanded CIK cells suppressed colony growth of autologous CML blast cells and myeloid progenitor cells. Allogeneic CIK cells from normal donors also suppressed CML colony growth but did not inhibit growth of normal hematopoietic colonies. Twelve of the 13 cultures were exclusively composed of Philadelphia (Ph)-negative cells and one culture had 1 out of 20 Ph-positive metaphases after 4 weeks in culture. Intracellular cytokine production was assayed by fluorescence-activated cell sorter (FACS), and the expanded T-cell cultures produced IL-2, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), but not IL-4. Both the CD4(+) and CD8(+) subsets secreted this cytokine profile. To test the in vivo activity of the expanded CIK cells, CML was engrafted into severe combined immunodeficiency disease (SCID) mice using matrigel. After 4 weeks, 4 x 10(7) autologous CIK cells were injected intravenously by tail vein injection into groups of mice, and the animals were sacrificed after a total of 18 weeks. Bcr-abl was detected in the bone marrow or spleen of 5 out of 6 control mice and only 2 out of 13 mice who received the autologous CIK cells (P = .02). In an additional series of animals, the mice did not engraft with CML but instead developed large human Epstein-Barr virus-associated lymphomas by 12 weeks. The mice who received autologous CIK cells at 4 weeks had either no tumor (5) or small tumors (5), whereas all 10 mice that received CIK cells at week 8 developed lymphomas; however, these were not as large as in the 10 control mice who did not receive CIK cells (P = . 03). This study shows that CIK cells, which are Ph chromosome-negative, can be expanded from patients with CML and have potent in vitro and in vivo efficacy against autologous tumor cells.
Animals↗
Learning impairment induced by lesion of the CA1 field of the primate hippocampus: attempts to ameliorate the impairment by transplantation of fetal CA1 tissue.
Monkeys with bilateral excitotoxic lesion of the CA1 field of the hippocampus were severely impaired at learning visuospatial conditional tasks. This was not a general spatial impairment, because the animals were not impaired on serial spatial reversal, which requires response flexibility in the spatial domain; they were not impaired at learning to choose the position furthest away from a single stimulus, which requires analysis of spatial layout of the test area, and they were not impaired at discriminating between two patterns that differed only in orientation. CA1-lesioned monkeys were impaired at learning a visuospatial conditional task when trials of the two component types "if AA go left" and "if BB go right" were presented according to either a pseudorandom or alternating schedule; but they were not impaired if one component type of trial was presented until three consecutive correct responses were made, followed by the other type of trial, to three consecutive correct responses. In all cases testing continued until a criterion of 27 of 30 consecutive correct responses across both types of trial was achieved. Although this suggests that CA1-lesioned animals are particularly prone to interference effects, they had no difficulty in learning ten concurrent visual discriminations presented against either a uniform background or with each discrimination presented against its own distinctive background, a condition that might reduce interference in unoperated monkeys. Interference following hippocampal damage might occur at a deeper level than stimulus identification such that animals with hippocampal damage may be able to learn about many aspects of different stimuli in parallel but may be unable to learn about multiple related aspects of the same subject matter. Monkeys with grafts of fetal CA1 tissue in the lesioned CA1 field showed significant improvement relative to CA1-lesioned animals on those tasks on which CA1-lesioned animals were impaired, although they remained impaired relative to control animals. This suggests that the grafts had produced some improvement in performance. Grafted monkeys did not differ from unoperated control monkeys or from CA1-lesioned monkeys on those tasks that were not sensitive to CA1 damage. This demonstrates that the grafts did not have an additional deleterious effect on cognitive performance.
Animals↗
Learning impairments following injection of a selective cholinergic immunotoxin, ME20.4 IgG-saporin, into the basal nucleus of Meynert in monkeys.
Four groups of monkeys (Callithrix jacchus) were injected with saline or increasing amounts of the immunotoxin, ME20.4 IgG-saporin, directly into the basal nucleus of Meynert via a frontal trajectory which avoided damage to the overlying basal ganglia. ME20.4 IgG binds to the primate p75 low-affinity neurotrophin receptor, when the saporin derivitized antibody is injected into the basal forebrain, it selectively destroys the magnocellular neurons of the basal nucleus of Meynert which are the cells of origin of the cholinergic projection to the neocortex. The highest dose of ME20.4 IgG-saporin produced a significant impairment on acquisition of a perceptually difficult visual discrimination. There was no significant effect on retention of tasks learnt before or after surgery, nor on concurrent acquisition of several perceptually easy discriminations or serial reversal of an easy discrimination. These results suggest that the impairment is not due to visual, motor or motivational difficulties and does not consist of difficulties with the formation of reward associations. Rather the impairment is largely confined to acquisition of perceptual discriminations. There was a significant correlation between the density of ME20.4 immunostaining in the basal nucleus of Meynert and the density of acetylcholinesterase histochemical staining in the frontal and temporal cortex and an inverse correlation between both of these and the degree of learning impairment in the animals. Lesioned animals also showed significant impairment on acquisition and reversal of perceptually easy discriminations when treated with a dose of scopolamine which did not impair performance in control animals. These results provide further evidence that cortical cholinergic neurotransmission contributes to certain forms of learning. The availability of a selective cholinergic immunotoxin effective in primates provides an important new tool for the study of cholinergic function and its involvement in ageing, Alzheimer's disease and other pathological states.
Animals↗
Characterisation of expression of mDMAHP, a homeodomain-encoding gene at the murine DM locus.
We examined the expression of the murine homologue of myotonic dystrophy associated homeodomain protein (mDMAHP) using two different strategies. The first approach, RT-PCR, detected spliced transcripts in a wide range of embryonic and adult tissues, in a pattern overlapping substantially with the expression of mDMPK. A second approach, the generation of transgenic mice expressing the lacZ reporter gene from a 4.3 kb promoter fragment, also demonstrated expression in a range of tissues with potential links to the phenotype in myotonic dystrophy. We conclude that murine DMAHP has a similar pattern of expression to human DMAHP and will serve as a useful model for functional studies of this gene, although species differences, such as the reduced CpG island (1.8 kb compared with 3.5 kb) must be carefully considered.
Age Factors↗
Transferrin and its receptor in the development of genetically determined neural tube defects in the mouse embryo.
The iron-binding growth factor transferrin is taken up and localised in the hindgut of midgestation mouse embryos. We investigated whether the distribution of transferrin may be disturbed in mutant curly tail embryos, a proportion of which exhibit a cell proliferation defect affecting the hindgut endoderm, as part of the pathogenetic sequence leading to development of neural tube defects. Immunostaining revealed a reduction in the binding and/or uptake of transferrin by hindgut epithelial cells in affected curly tail embryos compared with their unaffected littermates. There was no apparent difference between the two embryo types, however, in the distribution or level of expression of the transferrin receptor. The receptor is expressed specifically in the hindgut endoderm of the 10.5-day embryo, although its mRNA is present in all tissues of the posterior neuropore region, suggesting posttranscriptional control of gene expression. These findings may indicate a role for transferrin binding and/or uptake in the regulation of cell proliferation in the hindgut endoderm, with a defect in this process in the curly tail mutant. However, an alternative explanation is suggested by our finding that transferrin immunostaining is more intense in the hindgut of unaffected curly tail embryos than in nonmutant CBA/Ca and CD-1 embryos. Thus, mutant embryos may increase their uptake of transferrin in an attempt to compensate for defective cell proliferation in the hindgut resulting from a defect in another pathway. Only a proportion of embryos are able to mount this compensatory response leading to the observed partial penetrance of developmental defects in the curly tail mutant mouse.
Animals↗
Transplantation of enriched and purged peripheral blood progenitor cells from a single apheresis product in patients with non-Hodgkin's lymphoma.
High-dose chemotherapy with or without radiotherapy followed by autologous transplantation of hematopoietic progenitor cells is an effective treatment for patients with high-risk or relapsed non-Hodgkin's lymphoma. Chemotherapy and/or hematopoietic growth factors have been used to mobilize progenitor cells in the peripheral blood for transplantation. However, the mobilized blood cell products have been found to be frequently contaminated with tumor cells, and techniques have not been developed to purge tumor cells from these products. In addition, the minimum number of hematopoietic progenitor cells required for engraftment has not yet been fully elucidated. We treated 21 patients with a single infusion of cyclophosphamide (4 g/m2) followed by daily administration of granulocyte colony-stimulating factor (G-CSF). After recovery of the white blood cell count, a single 3-hour apheresis collection was performed. The apheresis product was then applied to a discontinuous Percoll gradient. The low-density fractions resulting from this separation procedure were enriched for CD34+ progenitor cells (total cell yield, 19.5%; CD34+ cell recovery, 81.2%). These enriched cellular products were treated with a panel of anti-B cell or anti-T cell monoclonal antibodies and complement in an effort to remove residual tumor cells. After treatment of the patient with myeloablative therapies, the enriched and purged cells were reinfused. Hematologic recovery was rapid, with median neutrophil engraftment in 10 days [absolute neutrophil count (ANC), greater than 0.5 x 10(9)/L] and 11 days (ANC, greater than 1.0 x 10(9)/L). Median platelet transfusion independence required 13 days. The rapidity of multilineage engraftment correlated with the number of CD34+ cells per kilogram that were infused. Patients who received more than 2 x 10(6) CD34+ cells per kilogram had rapid hematologic engraftment, whereas those patients transplanted with less than 2 x 10(6) CD34+ cells per kilogram had slower platelet recovery. Modeling studies using a lymphoma cell line with a t(14; 18) chromosomal translocation demonstrated the successful removal of tumor cells assayed using the polymerase chain reaction (PCR) after the processing and purging. Four of the 21 patients had PCR-detectable lymphoma cells in the bone marrow and peripheral blood; however, the enriched and purged blood products reinfused in all four did not contain detectable tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
Autografting for patients with CML in chronic phase: an update. Hammersmith BMT Team LRF Centre for Adult Leukaemia.
Between 1984 and 1992, 21 patients with chronic myeloid leukaemia (CML) in chronic phase (CP) were treated with high-dose chemotherapy (or chemoradiotherapy) followed by autografting with unmanipulated peripheral blood stem cells (PBSC). 12 of these patients survive at a median of 82 months from the time of autografting (range 9-105 months). Nine patients died, six of leukaemia in transformation and three from other causes. Survival of these 21 autograft patients was compared to that of 636 age-matched controls on the Medical Research Council's (MRC) data base, who had been treated with conventional chemotherapy over the same period. Autografted patients had a significantly longer survival at 5 years post autograft than chemotherapy patients (56% v 28%) even after appropriate allowance for time at risk before autograft (Mantel-Byar, 2P = 0.003). There was no difference in survival whether autografting was performed early in the disease or later or whether the PBSC had been harvested soon after diagnosis or later. If the benefits of autografting in chronic phase seen in this non-randomized series can be confirmed in a randomized study, autografting might be the treatment of choice for younger CML patients who do not have suitable donors for allogeneic transplant.
Adult↗
Life-threatening infections occurring more than 3 months after BMT. 18 UK Bone Marrow Transplant Teams.
We sent a questionnaire to 22 teams performing allogeneic and autologous bone marrow transplants (BMT) in the UK enquiring about routine use of prophylactic antimicrobials post-transplant, use of CMV-negative blood products and the incidence of major infection acquired more than 3 months post-BMT. Eighteen centres (82%) responded. To prevent Pneumocystis infection 17 centres routinely gave cotrimoxazole at various doses for periods varying between 3 and 12 months (or sometimes longer if chronic GVHD was present) and six centres gave nebulised pentamidine to patients intolerant of cotrimoxazole. Six centres gave penicillin for 1-3 years to allograft patients. Thirteen centres gave only CMV-negative blood products to CMV neg/neg patients, one centre gave CMV immunoglobulin and five centres continued acyclovir to 6 months. During the period 1986-90, 818 autologous and 1007 allogeneic BMT patients were reported, of whom 113 (6.2%) developed severe infections requiring readmission to hospital. The commonest infections were CMV (n = 19), Pneumocystis (n = 12), Pneumococcus (n = 15), Pseudomonas (n = 7) and Aspergillus (n = 8). Some patients with severe infections were not receiving 'appropriate' prophylaxis. Only two of the patients with Pneumocystis were taking cotrimoxazole. We conclude that the duration of continuing prophylaxis against Pneumocystis and pneumococcal infections after BMT needs careful consideration; prophylaxis may be especially important in patients with persisting immune suppression.
Aspergillosis↗
Autografting for patients with chronic myeloid leukemia--the Hammersmith experience.
The optimal approach for curing patients with chronic myeloid leukemia (CML) in chronic phase (CP) is an allogeneic bone marrow transplant (BMT). However, this approach is not available to the majority of patients. Autografting, using either purged or unpurged bone marrow or peripheral blood stem cells (PBSC), could be beneficial for patients who are not eligible for BMT. Between 1984 and 1992, 21 patients with CML in CP were autografted using unmanipulated PBSC harvested either at diagnosis or thereafter. Ten of 21 patients survived at a median of 84 months following autografting (range: 12-108 months). Eleven patients died, seven of blast transformation and four from other causes. The timing of the autograft or the harvest does not appear to have a bearing on survival.
Bone Marrow Transplantation↗
Pyomyositis in a patient with myeloma responding to antibiotics alone.
Pyomyositis is a rare purulent infection of skeletal muscle with striking clinical features. It usually occurs in patients living in the tropics but is increasingly being reported in immunosuppressed patients. The traditional approach to management has been surgical with drainage and debridement of the multiple muscle abscesses. We report a patient with myeloma who developed multiple muscle and lung abscesses associated with a Staphylococcus aureus septicaemia. The case was successfully managed with intravenous antibiotics alone with no recurrence of the abscesses during a later episode of neutropenia. The advantages of avoiding surgical intervention in immunosuppressed and thrombocytopenic patients are obvious.
Abscess↗
Peripheral blood stem cell autografts in CML.
The treatment of patients with CML in chronic phase by high dose chemotherapy followed by transfusion of autologous haemopoietic stem cells collected and cryopreserved previously may theoretically prolong survival. This benefit could result from reducing the number of leukaemia stem cells at risk for transformation or by partial re-establishment of Ph-negative haematopoiesis. In practice some patients achieve partial Ph-negative haematopoiesis after autografting but most patients have entirely Ph-positive haematopoiesis by one year after autografting. Results may be improved if methods to favour reconstitution with Ph-negative haematopoiesis can be perfected.
Antigens, CD↗
Development of left/right handedness in the chick heart.
The chick heart tube develops from the fusion of the right and left areas of precardiac mesoderm and in almost all cases loops to the embryo's right-hand side. We have investigated whether any intrinsic difference exists in the right and left areas of precardiac mesoderm, that influences the direction of looping of the heart tube. Chick embryos incubated to stages 4,5 and 6 were cultured by the New method. Areas of precardiac mesoderm were exchanged between donor and host embryos of the same stage and different stages to form control, double-right and double-left sided embryos. Overall, double-right sided embryos formed many more left-hand loops than double-left sided embryos. At stages 4 and 5 a small percentage of double-right embryos formed left-hand loops (13%) whereas at stage 6 almost 50% of hearts had left-hand loops. Control embryos formed right-hand loops in 97% of cases. The stability of right-hand heart looping by double-left sided embryos, may be related to the process of 'conversion', whereas the direction of looping by double-right sided embryos has become randomised. There is some indication that an intrinsic change occurred in the precardiac mesoderm between stages 5 and 6 that later influenced the direction of looping of the heart tube. The direction of body turning is suggested to be linked to the direction of heart looping.
Animals↗
Dual infection with Pneumocystis carinii and respiratory viruses complicating bone marrow transplantation.
Pneumonia due to dual infection with Pneumocystis carinii and respiratory viruses is a rare but formidable complication of bone marrow transplantation. We report here two cases of viral infections complicating P. carinii pneumonia in bone marrow transplant recipients who, at the time of infection, were not taking P. carinii prophylaxis. Both patients died following the pneumonia. Potential factors contributing to the dual infection included graft-versus-host disease, high-dose steroids and cyclosporin A. P. carinii prophylaxis should be continued for 12 months, or longer in bone marrow transplant recipients requiring prolonged immunosuppressive therapy. As specific antiviral therapy becomes available for some respiratory viral infections, performing regular viral surveillance cultures and responding with active early treatment may help improve the outcome in these immunocompromised patients.
Adenovirus Infections, Human↗
Acquired beta thalassaemia trait in MDS.
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Adult↗